Project 1 SUMMARY/ABSTRACT High-risk precancerous lesions (complex atypical hyperplasia, CAH) and grade 1 non-invasive endometrioid endometrial cancer (EEC) are typically treated by total hysterectomy and bilateral salpingo- oophorectomy; however, there is an increasing need for conservative treatment. Conservative therapy is particularly important for two groups of patients, 1) morbidly obese women with high surgical risks, and 2) premenopausal women who wish to maintain fertility. In fact, the Gynecologic Cancer InterGroup has recently identified conservative therapy for these patients as a key unmet clinical need that should be prioritized for research. Moreover, these two groups make up a significant portion of EEC patients. Obesity is a strong risk factor for EEC, and it is estimated that 12-17% of women with EEC are morbidly obese, with this percentage likely to increase as the obesity epidemic continues. In addition, approximately 20% of EEC cases occur in premenopausal women, for whom fertility-preservation may be desired. Progesterone is known to counteract the effects of estrogen in the endometrium, and our studies have shown that a progestin-eluting intrauterine device (levonorgestrel IUD) is effective against only 50% of grade 1 cancers. Preclinical studies and clinical trials in recurrent EEC have shown that mTOR inhibition (via everolimus) in combination with blocking estrogen signaling may further improve response rates. We will conduct a phase II clinical trial of levonorgestrel IUD alone or in combination with oral everolimus. We predict that targeting this dual pathway approach will significantly improve clinical responses in early EEC. We will then leverage advanced molecular profiling technologies using microdissected stromal and epithelial components of endometrial tissue samples to identify aberrations that are associated with levonorgestrel IUD- responsive CAH and grade 1 disease versus levonorgestrel IUD-resistant disease (including subgroups of everolimus responders and everolimus non-responders). Our studies will also evaluate endometrial stroma- gland crosstalk signaling in treatment response. These highly translational studies will define profiles for high- risk subgroups that warrant combination treatment with everolimus and potentially identify additional molecular targets for future studies focused on cancer prevention and therapeutics. Our overall goal is to ensure that conservative management is an effective clinical option. For this reason, we are developing and optimizing a polymer-based intrauterine drug delivery system to improve tolerability of conservative therapy. We propose that intrauterine drug delivery can enable long-term sustained intrauterine administration of everolimus without toxicities related to systemic administration. Overall, this project uses the combined expertise of clinical and basic science research to rapidly advance translational studies to improve clinical approaches to conservative therapy in CAH and grade 1 EEC.